Vitamin D inhibits COX-2 expression and inflammatory response by targeting thioesterase superfamily member 4

J Biol Chem. 2014 Apr 25;289(17):11681-11694. doi: 10.1074/jbc.M113.517581. Epub 2014 Mar 10.

Abstract

Inadequate vitamin D status has been linked to increased risk of type 2 diabetes and cardiovascular disease. Inducible cyclooxygenase (COX) isoform COX-2 has been involved in the pathogenesis of such chronic inflammatory diseases. We found that the active form of vitamin D, 1,25(OH)2D produces dose-dependent inhibition of COX-2 expression in murine macrophages under both basal and LPS-stimulated conditions and suppresses proinflammatory mediators induced by LPS. Administration of 1,25(OH)2D significantly alleviated local inflammation in a carrageenan-induced paw edema mouse model. Strikingly, the phosphorylation of both Akt and its downstream target IκBα in macrophages were markedly suppressed by 1,25(OH)2D in the presence and absence of LPS stimulation through up-regulation of THEM4 (thioesterase superfamily member 4), an Akt modulator protein. Knockdown of both vitamin D receptor and THEM4 attenuated the inhibitory effect of 1,25(OH)2D on COX-2 expression in macrophages. A functional vitamin D-responsive element in the THEM4 promoter was identified by chromatin immunoprecipitation and luciferase reporter assay. Our results indicate that vitamin D restrains macrophage-mediated inflammatory processes by suppressing the Akt/NF-κB/COX-2 pathway, suggesting that vitamin D supplementation might be utilized for adjunctive therapy for inflammatory disease.

Keywords: Cyclooxygenase (COX) Pathway; Lipopolysaccharide (LPS); Macrophages; NF-kappa B (NF-KB); VDR; Vitamin D.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Base Sequence
  • Calcitriol / pharmacology*
  • Carrageenan / toxicity
  • Cell Line
  • Cyclooxygenase 2 / genetics*
  • DNA Primers
  • Enzyme-Linked Immunosorbent Assay
  • Fatty Acids, Nonesterified / metabolism
  • Gene Expression Regulation, Enzymologic / drug effects*
  • Humans
  • Inflammation / chemically induced
  • Inflammation / prevention & control*
  • MAP Kinase Signaling System / drug effects
  • Macrophages / drug effects
  • Macrophages / enzymology
  • Macrophages / metabolism
  • Mice
  • Mice, Inbred C57BL
  • Mice, Knockout
  • Phosphorylation
  • Prostaglandins / biosynthesis
  • Reverse Transcriptase Polymerase Chain Reaction
  • Thiolester Hydrolases / metabolism*

Substances

  • DNA Primers
  • Fatty Acids, Nonesterified
  • Prostaglandins
  • Carrageenan
  • Cyclooxygenase 2
  • Thiolester Hydrolases
  • Calcitriol